HYLS1

HYLS1 centriolar and ciliogenesis associated

Basic information

Region (hg38): 11:125883613-125900646

Links

ENSG00000198331 ∙ NCBI:219844 ∙ OMIM:610693 ∙ HGNC:26558 ∙ Uniprot:Q96M11 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hydrolethalus syndrome 1 (Definitive), mode of inheritance: AR
• hydrolethalus syndrome 1 (Strong), mode of inheritance: AR
• Joubert syndrome (Supportive), mode of inheritance: AR
• hydrolethalus syndrome (Supportive), mode of inheritance: AR
• hydrolethalus syndrome 1 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hydrolethalus syndrome	AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Cardiovascular; Craniofacial; Genitourinary; Musculoskeletal; Neurologic; Pulmonary	7028327; 15843405; 18648327

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HYLS1 gene.

• not provided (190 variants)
• Inborn genetic diseases (37 variants)
• Hydrolethalus syndrome (30 variants)
• Severe growth deficiency-strabismus-extensive dermal melanocytosis-intellectual disability syndrome (14 variants)
• Hydrolethalus syndrome 1 (13 variants)
• not specified (4 variants)
• Dandy-Walker syndrome (2 variants)
• Genetic syndrome with a Dandy-Walker malformation as major feature;Severe growth deficiency-strabismus-extensive dermal melanocytosis-intellectual disability syndrome (1 variants)
• - (1 variants)
• PUS3-related condition (1 variants)
• Severe growth deficiency-strabismus-extensive dermal melanocytosis-intellectual disability syndrome;Genetic syndrome with a Dandy-Walker malformation as major feature (1 variants)
• Anencephaly;Heart, malformation of;Polyhydramnios;Ankle flexion contracture;Aplasia/Hypoplasia of the cerebellum (1 variants)
• Aplasia/Hypoplasia of the cerebellum;Heart, malformation of;Polyhydramnios;Anencephaly;Ankle flexion contracture (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HYLS1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				92	1	93
missense	1		17	1	3	22
nonsense		2	2			4
start loss						0
frameshift			2			2
inframe indel			7			7
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding	4	8	69	25	15	121
Total	5	10	97	118	19

Highest pathogenic variant AF is 0.000945

Variants in HYLS1

This is a list of pathogenic ClinVar variants found in the HYLS1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
11-125883645-G-A		Hydrolethalus syndrome	Uncertain significance (Jun 14, 2016)
11-125891423-G-GT		Hydrolethalus syndrome	Uncertain significance (Jun 14, 2016)
11-125891423-G-GTT		Hydrolethalus syndrome	Benign (Jun 14, 2016)
11-125891423-G-GTTT		Hydrolethalus syndrome	Uncertain significance (Jun 14, 2016)
11-125891480-A-AT		Hydrolethalus syndrome	Uncertain significance (Jun 14, 2016)
11-125891481-T-TTG		Hydrolethalus syndrome	Uncertain significance (Jun 14, 2016)
11-125891482-T-TA		Hydrolethalus syndrome	Uncertain significance (Jun 14, 2016)
11-125891482-T-TG		Hydrolethalus syndrome	Uncertain significance (Jun 14, 2016)
11-125891482-T-TAA		Hydrolethalus syndrome	Uncertain significance (Jun 14, 2016)
11-125891482-T-TTA		Hydrolethalus syndrome	Uncertain significance (Jun 14, 2016)
11-125891483-G-GA		Hydrolethalus syndrome	Uncertain significance (Jun 14, 2016)
11-125891483-G-GAA		Hydrolethalus syndrome	Benign (Jun 14, 2016)
11-125893822-C-T			Uncertain significance (Aug 21, 2022)
11-125893827-C-T			Likely benign (Dec 11, 2023)
11-125893851-C-G		Severe growth deficiency-strabismus-extensive dermal melanocytosis-intellectual disability syndrome	Benign (Jan 31, 2024)
11-125893862-G-A			Likely benign (Apr 09, 2018)
11-125893870-T-C		Inborn genetic diseases	Uncertain significance (Oct 03, 2022)
11-125893892-TTTC-T			Uncertain significance (Jul 14, 2022)
11-125893903-T-C		Inborn genetic diseases	Uncertain significance (Sep 20, 2023)
11-125893911-A-G			Likely benign (Sep 27, 2022)
11-125893924-A-G		Inborn genetic diseases	Uncertain significance (Mar 06, 2023)
11-125893928-G-A		Severe growth deficiency-strabismus-extensive dermal melanocytosis-intellectual disability syndrome	Pathogenic (Mar 14, 2024)
11-125893930-C-T		Inborn genetic diseases	Uncertain significance (May 11, 2022)
11-125893935-A-G			Likely benign (Aug 09, 2022)
11-125893936-C-T			Uncertain significance (Dec 02, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HYLS1	protein_coding	protein_coding	ENST00000425380	1	17035

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.32e-9	0.146	125675	0	73	125748	0.000290

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.177	161	167	0.962	0.00000943	1932
Missense in Polyphen		50	60.806	0.82229		664
Synonymous	0.147	55	56.4	0.975	0.00000263	606
Loss of Function	0.298	14	15.3	0.918	0.00000118	136

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000911	0.000911
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000308	0.000308
Middle Eastern	0.0000544	0.0000544
South Asian	0.000261	0.000261
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Plays a role in ciliogenesis. {ECO:0000250|UniProtKB:A0A1L8ER70, ECO:0000250|UniProtKB:Q95X94}.
• Disease: DISEASE: Hydrolethalus syndrome 1 (HLS1) [MIM:236680]: A lethal syndrome characterized by polydactyly, central nervous system malformation, and hydrocephalus. The polydactyly is postaxial in the hands and preaxial in the feet. A highly characteristic hallux duplex is seen in almost no other situation. In half of the cases, a large atrioventricular communis defect of the heart is found. The pregnancy is characterized by hydramnios, which is often massive, and by preterm delivery. {ECO:0000269|PubMed:15843405}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in HYLS1 may be involved in ciliopathies other than hydrolethalus syndrome 1. A homozygous mutation resulting in a C-terminal extension of 11 residues has been found in patients diagnosed as Joubert syndrome, a ciliopathy presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy and renal disease. {ECO:0000269|PubMed:26830932}.

Recessive Scores

• pRec: 0.167

Intolerance Scores

• loftool: 0.565
• rvis_EVS: -0.03
• rvis_percentile_EVS: 51.66

Haploinsufficiency Scores

• pHI: 0.115
• hipred: N
• hipred_score: 0.144
• ghis: 0.524

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: H
• gene_indispensability_pred: E
• gene_indispensability_score: 0.752

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Hyls1

Gene ontology

• Biological process: cilium assembly
• Cellular component: nucleus;cytoplasm;centrosome;centriole;cytosol;plasma membrane;cilium;non-motile cilium
• Molecular function: protein binding